Among the agents recently proposed for minimizing skin irritation due to skin irritants are fibers (Creton, I., 2002. U.S. Patent Appl., 20020182238A1), and an immune suppressant such as a composition that blocks CD1d activation (Wilson, S. B., 2002. U.S. Patent Appl., 20020165170A1), discloses a method that blocks antigen presentation by skin located immune cells. Lacharriere et al., have proposed the use of a histamine antagonist and or a TNF-alpha antagonist (Lacharriere, O. De; et al., 2001 in U.S. Appl., No.: 20010022978A1).
Historically, plants have been an important source of both new pharmaceuticals and new cosmetic ingredients. Even today plants have yield more new medicinal compounds and cosmetic ingredients than the chemical synthesis approaches exemplified by the recent reliance on combinatorial chemistry methods (C&EN, Oct. 13, 2003).
The search for novel natural products from plants has led to a worldwide search for exotic plants in tropical rainforests of the Amazon and to the ocean depths. This has produced an array of new plant oils that fill the catalogs of commercial cosmetic ingredient suppliers, and to the harvesting of bacteria that inhabit temperature extremes for the purposes of isolating their heat stable enzymes. Yet, it must be noted, that the screening of higher plants for their useful drugs and cosmetic active ingredients has barely scratched the surface of the more than 250,000 species of flowering plants (Angiosperms), and very few of the 50,000 species of monocots (grasses and ornamentals) relatives to the 200,000 species of dicot herbs, shrubs, trees, and ornamentals). Below the flowering plant, aside from a few hallucinogenic mushrooms, and algal plants and bacteria that produce abundance polysaccharide gums, the realm of other plant phyla has been totally neglected. Aside from the lethal phytotoxins from red tides caused by unicellular Dinoflagellates, none of the highly diverse unicellular plants algae have been screened for useful drugs and cosmetics. Thus, it fair to conclude that a systematic and rationale approach to this task has yet to be formulated.
The inventor has taken a different approach to the search for novel botanicals, i.e., plants with medicinal or cosmetic value. This approach narrows the search to plants that grow in the wild, and are cultivated primarily as a foodstuff but for which there is no present commercial medicinal or cosmetic uses. This has led to the discovery of many novel sources of plant derived anti-oxidants some of which are also anti-irritants
A truly effective anti-irritant strategy seeks to modulate checkpoints in the irritant signal cascade. Earlier, Wille & Kydonieus (2000) reviewed the scientific and patent literature on anti-irritants. The aim of which was to find new agents useful in prevention and treatment of contact irritant due to topical cosmetic, dermatological and transdermal drugs. In a series of patents (Wille, U.S. Pat. No. 6,670,395, 2003; Wille, U.S. Pat. No. 5,716,987, 1998; Wille and Kydonieus, U.S. Pat. No. 5,843,979, 1998; Wille, Kydonieus and Castellan, U.S. Pat. No. 5,618,557, 1997; Wille and Kydonieus, U.S. Pat. No. 5,686,100, 1997; Wille and Kydonieus, U.S. Pat. No. 5,912,010, 1999; Wille, Kydonieus and Castellana, WO Pat. No. 9,718,782, 1997; Wille and Kydonieus, European Pat. No. 5,612,525, 1994; and in reports (Kalish R, Wood J, Wille J, and Kydonieus A, 1995; Wille, J J., Kydonieus, A., and Kalish, R S., 1998; Wille, J J., Kydonieus, A., and Kalish, R S., 1999a; Wille, J J, Kydonieus, A F., and Murphy, G F., 1999b; Wille, J J., Kydonieus, A F, and Kalish, R S., 2000; Wille and Kydonius, 2001; Wille, Kydonieus and Castellana, WO Pat. No. 9,718,782, 1997), it was shown that ion channel modulators and mast cell degranulating agents were effect anti-irritants and counter-sensitizers. Ethacrynic acid (Edacrinn, Merck) was effective in preventing contact sensitization due to the delivery to mouse skin of four sensitizing drugs: Clonidine, Chlorpheniramine, Albuterol, and Nadolol. Ethacrynic acid, a potassium ion channel blocker, was also effective in preventing skin irritation due to the topical application to mouse of 2,4-dinitro-chlorobenzene, arachidonic acid, phorbol myristic acid, trans-retinoic acid, and lactic acid. The calcium ion channel blockers Nifedipine and Verapamil were effective in minimize contact sensitization in mouse skin due to topical application of the sensitizing and transdermally delivered drug, Nadolol. Phenoxyacetic acid and its alkyl derivatives, non-drug analogs of the diuretic, ethacrynic acid, were shown to prevent contact sensitization due to application to mouse skin of the sensitizing hair dye, para-phenylenediamine and to block skin irritation due a panel of known skin irritants, including anionic surfactants such as sodium lauryl sulfate. Finally, agents which induce mast cell degranulation such as cis-urocanic acid and capsaicin were reported to prevent contact sensitization in a mouse skin model.
Natural products and plant extracts have been the focus of recent interest as emollients and anti-irritants. Castro J (1995) in U.S. Pat. No. 5,393,526 discloses Rosmarinic acid (5%), derived from Sage plant, was able to reduce by more than three-fold the irritating action of alpha-hydroxy acids (lactic and glycolic acids). Pretreatment, one-half hour prior to application of cosmetic formulation containing known skin irritants, by para-aminobenzoic acid and balsam of Peru with extracts the Cola nitida plant, have been disclosed in European Pat. No. Application 0,354,554A2 to prevent skin irritation. Oil from Yerba plants have also been claimed in World Pat. No. Application WO 9,114,441 to eliminate irritation and sensitization that accompanies topical, tranmucosal and transdermal delivery of dihydroergotamine mesylate, acetominophen, oxymetazoline, diphenhydramine, nystatin, clindamycin, and para-aminobenzoic acid. Oils of chamomile, containing chamazulene isolated from yarrow, chamomile and wormwood, were disclosed in U.S. Pat. No. 4,908,213 to be good antipuretics when co-administered in transdermal Nicotine patches.
Depletion of antioxidants is known to cause oxidative damage to human skin (Podda et al, 1998). As discussed above, flavonoids are known to be potent anti-oxidants. Topical replacement of skin anti-oxidants may help to alleviate damage due to ultraviolet radiation and ozone exposure. Flavonoids require stabilization against oxidation by addition of co-reductants such as Vitamin E (α-tocopherol) or Vitamin C (Ascorbic Acid). No mechanism exists to reduce oxidized Vitamin E since there is no Ascorbic acid in the upper layers of the epidermis (stratum corneum). Lazendorfer et al., (2002) in U.S. Pat. No. 6,423,747 discloses cosmetic and dermatological preparations with favonoids having anti-oxidant properties. Illustrative examples mention standard water-in-oil and oil-in-water formations without providing any evidence of their efficacy in these formulations.
Of particular importance to the category of polyphenols and flavonoids is the demonstration (Wille, 2003) that the mechanism of action for many plant-derived anti-irritants is their inhibition of protein tyrosine kinases associated with growth factor receptor stimulated autocrine control of cell proliferation that is the hallmark of many useful skin products that cause skin irritation, i.e., retinoic acid. The use of flavonoids as anti-irritants are among the plant-derived anti-irritants that are readily formulated in the novel hydrophobic delivery system claimed in this patent. They include many plants and herbs are rich in flavonoids as well as flavonoids present in Spanish Honeybee pollen. For example, rutin, quercetin, myricetin, and trans-cinnamic acid; all were present at >350 mg/100 g. Recently, it was reported (Bonina et al, 2002), that Kaempferol is the major flavonoid derived from lyophilized extracts of the flowering buds of capers (Capparis spinosa L). This material was shown to have both anti-oxidant and photo-protective effects in human skin.
Antioxidants and free radical scavengers have been employed in many patented formulations for eliminating or minimizing irritation and contact sensitization reactions. Inhivbitors of the metabolites of the arachidonic acid cascade known to be involved in the irritant mechanism of skin have been claimed in European Pat. No. EP 0,314,528A1. Among the designated anti-irritants claimed were Vitamin E, BHT, para-tertiary butyl catechol, hydroquinone, benzoquinone, N,N-diethylhydroxyamine, and nordihydroguaiareic acid.
Vitamin C (ascorbic acid), a water soluble antioxidant, was disclosed in U.S. Pat. No. 5,516,793 to be effective in decreasing skin irritation caused by topical application of such ingredients as: a-hydroxy acids, benzoyl peroxide, retinal, retinoic acid, quaternary ammonium lactates, and salicylic acid. Vitamin E (α-tocopherol) is disclosed in U.S. Pat. No. 5,545,407 to reduce skin irritation caused by actives in dermatological preparations containing benzoyl peroxide., and in U.S. Pat. No. 5,252,604 it was disclosed that topical α-tocopherol reduced skin irritation due to repeated doses of retinoic acid. Another antioxidant panthenol and its derivatives pantothenic acid, pantethine and pantetheine have been claimed as anti-irritants for formulations containing up to 20% benzoyl peroxide.
The role of antioxidants in protecting the skin from harmful solar exposure, and photoaging is well known. In their book, “Oxidants and Antioxidant in Cutaneous Biology, Thiele and Elsner (2001) have assembled a comprehensive review of free radical chemistry in the skin and the antioxidant network of defense in the stratum corneum. Among the antioxidants discussed for protection of skin are Vitamins E and Vitamin C, green tea polyphenols, resveratol, curcumin, silymarin, ginger, and diallyl sulfide, all of which afford some protection against the development of skin cancer. In addition, the role of carotenoids (lycopenes, luein and α, and β-carotene) as dietary supplements in chemoprevention of cancer were reviewed. The protective effect of topical anti-oxidants against solar radiation result from e.g.: Vitamin E and Vitamin C. Other reported antioxidants that efficiently reduce photodamage include the thiol, N-acetylcysteine and α-lipoic acid, which may prevent oxidative stress in skin. In addition, plant-derived flavonoids (apigerneic genistein, catechin, epicatechin, a-glycosylrutin and silymarin) are polyphenols with good antioxidant activity.
Vitamins C and E are routinely used as antioxidants to either stabilize cosmetic ingredients or more recently for their anti-aging free-radical scavenging properties. The most widely used botanical with accepted anti-irritant activity are is Aloe gel; and Witch Hazel (Hammelis Water) containing polymeric proanthocyanidins is by far the best documented case of a botanical anti-irritant. Other botanically-derived actives with potential anti-irritant activity are the catechins and polyphenols, e.g., green tea leaves, and grape seed oil extracts. Additional antioxidants derived from botanicals are Bisabolol, Epigallocatechine, Epigallocatechinegallate Rutin, Quercetin, Hesperidin, Diomine, Mangiferin, Mangostin, Cyanidin chloride, Astaxanthin, Xanthophylls, Lycopene, Reversatrol, Tetrahydrodiferuloylmethane, Rosmarinic acid, Hypericin, Ellagic acid, Chlorogenic acid, Oleoeuropein, Thiotic acid, Glutathione, and Andrographolide (Gupta, 2001). Few of these have been rigorously shown to have anti-irritant activity. Nevertheless, the prospects for broadening the base of plant derived anti-irritants is tremendous because only a small fraction of the over 250,000 known Angiosperm species has been explored.
Here we claim the anti-irritant and antioxidant activity of several new plant-derived anti-irritants. They include a botanical anti-irritant isolated from corn plant tassels, dried lavender flowers, dried flowers of Hops plants, catkins of the Oak tree (Quercus sp.), catkins of the Linen tree (Tialia sp.), an extract from green tea leaves, green onion leaves; and extract from ripened Autumn Olive berries. These extracts have been incorporated into a novel carrier system (Wille, Novel Delivery Systems, 2004), especially designed to improve their cutaneous delivery.